U.S. patent application number 11/569473 was filed with the patent office on 2008-06-12 for method for the production of chemical and pharmaceutical products with integrated multicolumn chromatography.
This patent application is currently assigned to Bayer Technology Services GmbH. Invention is credited to Sebastian Bocker, Joern Greifenberg, Peter Jahn, Berthold Justen, Heinz Kansy, Karsten-Ulrich Klatt, Gerhard Noeth, Jochen Strube.
Application Number | 20080135483 11/569473 |
Document ID | / |
Family ID | 34967690 |
Filed Date | 2008-06-12 |
United States Patent
Application |
20080135483 |
Kind Code |
A1 |
Strube; Jochen ; et
al. |
June 12, 2008 |
Method For the Production of Chemical and Pharmaceutical Products
With Integrated Multicolumn Chromatography
Abstract
The invention relates to a chromatographic process for substance
separation in the context of the preparation of chemicals such as,
for example, chiral pharmaceuticals, isomers or biomolecules on the
small-scale and production scale, based on Simulated Moving Bed
(SMB=countercurrent chromatography) technology.
Inventors: |
Strube; Jochen; (Hagen,
DE) ; Klatt; Karsten-Ulrich; (Leverkusen, DE)
; Noeth; Gerhard; (Koln, DE) ; Greifenberg;
Joern; (Bergisch Gladbach, DE) ; Bocker;
Sebastian; (Leverkusen, DE) ; Kansy; Heinz;
(Koln, DE) ; Jahn; Peter; (Leverkusen, DE)
; Justen; Berthold; (Burscheid, DE) |
Correspondence
Address: |
NORRIS, MCLAUGHLIN & MARCUS, P.A.
875 THIRD AVE, 18TH FLOOR
NEW YORK
NY
10022
US
|
Assignee: |
Bayer Technology Services
GmbH
Leverkusen
DE
|
Family ID: |
34967690 |
Appl. No.: |
11/569473 |
Filed: |
May 14, 2005 |
PCT Filed: |
May 14, 2005 |
PCT NO: |
PCT/EP2005/005313 |
371 Date: |
October 18, 2007 |
Current U.S.
Class: |
210/656 |
Current CPC
Class: |
F16D 3/387 20130101;
F16B 11/00 20130101; Y10T 137/7062 20150401; B01D 15/1842 20130101;
F16K 27/003 20130101; F16D 2001/062 20130101; G01N 30/42 20130101;
F16D 1/068 20130101 |
Class at
Publication: |
210/656 |
International
Class: |
B01D 15/08 20060101
B01D015/08 |
Foreign Application Data
Date |
Code |
Application Number |
May 21, 2004 |
DE |
10 2004 025 000.6 |
Claims
1. A process for the separation of a substance mixture with the aid
of a countercurrent chromatography process, in which a substance
mixture to be separated and the eluent are continuously supplied to
a column circuit consisting of more than one chromatography columns
packed with an adsorbent and connected in series and in other
positions of the column circuit an extract stream comprising at
least one separated component, and a raffinate stream comprising at
least one other component are continuously removed and in which a
relative movement between a liquid, mobile phase consisting of the
substance mixture and the eluent and the adsorbent in solid phase
is produced by sequential opening of liquid addition and removal
positions along the columns, characterized in that only one eluent
supply pump and an eluent compensation container, but no
circulation pump is employed in the circulation.
2. The process as claimed in claim 1, characterized in that at most
4 pumps are employed in the chromatography circulation.
3. The process as claimed in claim 1, characterized in that at
least one discharge pump, extract or raffinate discharge, is
replaced by a control valve.
4. The process as claimed in claim 1, characterized in that an
automatic discharge of contaminated eluent in the circulation is
made possible by means of an online detection and a control
valve.
5. The process as claimed in claim 1, characterized in that the
accuracy of the mass flow control is increased by measurement of
the recyclate stream and the redundancy thus achieved by means of a
measured data balance.
6. The process as claimed in claim 1, characterized in that in the
mass flow regulation the adherence to the total mass balance is
achieved by means of a filling level regulation in the eluent
compensation container.
7. A modular valve technique (MVS), consisting of a master board,
on which at least one valve, consisting of a valve housing and a
control housing is installed, the control housing having an
internal pneumatic space which is divided into a lower control
space and an upper control space by a piston having a seal and the
lower control space being separated from the valve housing by a
closing plate and additional seals, an extended valve spindle being
present on the piston, which runs through the valve housing to the
seal seat in the area of the master board, the valve housing and
the control housing are fixed to one another using a centering
plate with seals, the valve housing having a second fixing, the
seal seat with associated seals is positioned on the master board
such that by means of a supply channel having a lateral transverse
channel in the master board a channel connection is provided by the
seal seat in the product space of the valve housing, where from the
product space in turn a discharge channel for the product discharge
is present, by which with the supply channel together a flow
channel is formed, furthermore, the valve spindle is bilaterally
extended to the piston such that on the one hand the valve spindle
reaches through the upper control space to outside the control
housing and on the other hand the valve spindle is extended through
the valve housing into the seal seat, the valve spindle having a
sealing contour to the valve seat and completely closing in the
closed position the extended transverse channel and preventing the
product flow.
8. The MVS as claimed in claim 6, characterized in that it is
constructed on a master board in the form of a hexagonal rod.
9. The process as claimed in claim 1, characterized in that at
least one valve system, as claimed in claim 6, is used.
10. A process for the preparation of a product, characterized in
that the product mixture derived from the reaction is fed directly
into a process as claimed in claim 1 and then worked up.
Description
[0001] The invention relates to a chromatographic process for
substance separation in the context of the preparation of chemicals
such as, for example, chiral pharmaceuticals, isomers or
biomolecules on the small scale and production scale, based on
Simulated Moving Bed (SMB=countercurrent chromatography)
technology.
[0002] SMB is a process which allows continuous substance
separations by imitating (simulating) the countercurrent between
the adsorbent and mobile phase (liquid, gas or in the supercritical
state).
[0003] U.S. Pat. No. 3,706,612 of A. J. de Rosset and R. W. Neuzil
describes a simulated moving bed (countercurrent chromatography)
unit on the pilot scale. Likewise, an operating problem is
described there when such units are operated on the large scale and
a circulating pump is utilized in order to guarantee the
circulation of the liquid in the process. This invention (U.S. Pat.
No. 3,706,612) describes the use of a valve at the starting end of
each adsorber bed in order to prevent an opposed flow.
[0004] U.S. Pat. No. 4,434,051 of M. W. Golem describes an
apparatus which allows countercurrent chromatography by utilizing a
large number of multiway valves instead of a single rotary
valve.
[0005] The separation of racemic mixtures on chiral adsorbents is
described in an article in the Journal of Chromatography, 590
(1992), pp. 113-117; an alternative arrangement of 8 adsorption
chambers and 4 rotary valves is utilized there.
[0006] U.S. Pat. No. 3,268,605 describes a control system which
controls the flow rate of three of the main streams by flow
regulators and the fourth stream by means of a pressure regulator.
A similar control concept for chiral substance systems is described
in WO 92/16274 of Bayer AG. This reference uses a number of two-way
valves in order to simulate the countercurrent of the
adsorbent.
[0007] In all these known techniques, however, the separating
capacity is impaired by the holdup volume of the circulation flow
pump, which must be compensated by additional measures, such as,
for example, asynchronous timing, alteration of the column lengths
or flow adjustment [such as, for example, in EP 0688590 A1,
Sepharex (Novasep), "Totvolumenkompensation der Kreislaufpumpe
durch Reduktion des Volumens" (Dead volume compensation of the
circulating pump by reduction of the volume) (Lange); "asynchronous
timing" as in EP 0688589 A1, Sepharex (Novasep); EP 0688588 A1
"Durchsatzanderung der Rezyklierpumpe" (Throughput alteration of
the recycling pump)]. In DE 19833502 A1 of Novasep, for this, the
SMB base regulation by means of pressure is described by
simultaneous variation of at least two throughputs.
[0008] Consequently, the asynchronous timing in one zone was
further developed to asynchronous timing in a number of or all
zones (WO 00/25885 A).
[0009] For example, WO 93/04022 A of Daicel in which SMB is
employed for resolution with subsequent re-racemization of the
unwanted isomer, or WO 91/13046 A of Daicel which likewise
describes the use of SMB with a chiral stationary phase for
resolution afford examples of the use of SMB technology.
[0010] The prior art for the regulation of the internal and
external mass flows in simulated countercurrent chromatography is
described, for example, in U.S. Pat. No. 4,499,115, U.S. Pat. No.
5,685,992, U.S. Pat. No. 5,762,806, EP 960642 A1 and DE 19833502
A1.
[0011] Customarily, for the transport of the fluids 5 pumps are
employed there, in each case one pump being located in the
corresponding supply and outlet lines--feed, eluent, extract and
raffinate lines, and a further pump is arranged within a closed
circuit. For the simulation of the solid countercurrent, after a
specific time interval, the timing period .tau., is retimed, i.e.
by means of appropriate valve circuits the addition and removal
sites are displaced around a column in the flow direction of the
fluid phase. The circulating pump thus "migrates" through the
individual zones and transports different volume flows during a
cycle.
[0012] FIG. 2 shows a customary SMB process. The fluid stream flows
on SMB operation in the circulation of a number of fixed bed
columns filled with adsorbent. The unit is subdivided into four
functional zones by the continuous addition or removal of the feed,
desorbent, extract and raffinate streams. Each one of these zones
here takes on a special separation or workup function. Also shown
is the recycle stream, transported by a recycle pump. Each
functional zone, between the positions of the external supply and
discharge streams, are in each case situated one to a number of
chromatographic columns. The concentration profile established on
suitable choice of the operating parameters in the cyclically
stationary state within the SMB unit of the main components to be
separated is shown schematically in the right section of FIG. 2
relative to the positions of the supply and discharge streams at
the point of time of the end of the cycle.
[0013] FIGS. 3 and 4 show schematically the apparatus construction
of a customary SMB process with the arrangement of individual
valves in two successive cycles. In the supply line of each column
2 individual valves for the switching of alternative feed or eluent
stream and in the outlet line of each column 3 individual valves
for alternative raffinate, extract or recycling stream. On each
further cycle, the valve circuits are displaced by one position to
the next column.
[0014] If the connecting lines between the columns are of different
length and contain a dead volume not to be neglected compared to
the column volume, this fact must be taken into account, and a
worsening of the separating capacity possibly associated therewith
must be counteracted. Asynchronous switching of the valves (EP
688589 B1), specific adjustment of the zone volumes (EP 688690 B2)
or an adjustment of the output of the circulating pump (EP 688588
B1) provide possible corrective measures.
[0015] For continuous operation as intended, the most exact
possible adherence to the internal and external mass flows is an
indispensable requirement. For this, customarily three of the four
supplied and discharged mass flows (Q.sub.F, Q.sub.D, Q.sub.Ex and
Q.sub.Raf) are constantly controlled, while the fourth part of the
flow is readjusted by means of a specified system pressure such
that this system pressure remains constant, by which the overall
mass balance is adhered to.
[0016] This so far customary mode of operation of SMB
chromatography units therefore has the following serious
disadvantages: [0017] The pressure regulation must on the one hand
compensate all malfunctions in the area of the mass flows as
quickly and exactly as possible, on the other hand it is itself in
some cases perceptibly disturbed by operation-related pressure
variations (e.g. also by the cyclical switching processes). In
particular in the case of high purity requirements and/or short
cycle times, this can lead to instabilities up to the loss of the
separating capacity. [0018] The locking of the mass balance by
means of pressure regulation requires a permanently closed
circulation. Short-term opening of the circulation, e.g. for the
discharge of impurities is thereby not possible. [0019] The
internal circulating pump is confronted with continuously changing
mass flows, in addition this type of switching causes variable dead
volumes and thus inherent process malfunctions, which must be
compensated. As already mentioned, this frequently proves to be
difficult, in particular in the case of short cycle times and
demanding separation tasks.
[0020] In circuit operation as intended, in the SMB process
generally 4 internal (Q.sub.I, Q.sub.II, Q.sub.III and Q.sub.IV)
and 4 external mass flows (Q.sub.F, Q.sub.D, Q.sub.Ex and
Q.sub.Raf) exist, which are linked to one another by means of the
following mass balances
Q.sub.I=Q.sub.D+Q.sub.IV
Q.sub.II=Q.sub.I-Q.sub.Ex
Q.sub.III=Q.sub.II+Q.sub.F
Q.sub.IV=Q.sub.III-Q.sub.Raf (1)
[0021] For the setting of the working point, 3 external and one
internal mass flow and the timing period .tau. must be specified in
such a way that the separating task is achieved and thereby
economical optimum operation is obtained with adherence to the
specified product purities. The timing period .tau. here determines
the "speed" of the apparent solid countercurrent.
[0022] In the entire prior art, for the operation of the SMB,
however, circulation pumps are fundamentally employed, which leads
to the problems already described due to the holdup volume of the
pump.
[0023] It has now surprisingly been found that contrary to
expectation no circulation flow pump is necessary in order to
maintain the fluid circulation in an SMB.
[0024] The present invention therefore relates to an SMB process in
which instead of the previously customary 5 pump concept a 4 pump
concept is used by pumping the eluent stream with constant flow and
extract, raffinate and feed stream. For the two outlet streams,
alternatively control valves instead of forced delivery pumps are
also possible here.
[0025] FIG. 1 shows the principle of the SMB chromatography unit
according to the invention. The unit is only shown schematically
here, for example the detailed line paths contained, the valve
circuits and the other instrumentation are absent. In addition, for
a better overview, the blocks shown in each case represent the
functional zones and not individual separating columns. The symbol
FI represents a continuous flow measurement, FIC and LIC represent
continuous flow or level regulations including the measuring and
control devices needed for this. Q, provided with different
indices, in each case represents a mass flow which occurs in a
certain position of the chromatography unit.
[0026] The circulation stream, as can be seen in FIG. 1, is
interrupted/separated by an intermediate container. In addition to
robust mass flow regulation, this additionally allows a discharge
of fractions containing potential impurities in the running
operation, which can be determined by suitable online analysis such
as, for example, UV, NIR, RI or US (in FIG. 1 marked as QIS). The
pump arranged in a fixed manner behind the intermediate container
here conveys the eluent stream with constant flow directly to the
first separating column of the SMB chromatography unit, mainly
independently of whether the eluent is discharged after flowing
through the unit or fed back in a closed circulation via the
intermediate container.
[0027] In order that a circulation flow pump is saved and an eluent
pump having constant flow is used, it is not necessary to
compensate the separating capacity-disrupting holdup volume of the
circulation flow pump by additional measures, such as, for example,
asynchronous timing, alteration of the column length or flow
adjustment (see prior art above). The further development of the
asynchronous timing in one zone to the asynchronous timing of a
number of or all zones is thus also superfluous, since the
separating capacity in the process according to the invention can
also already be achieved directly by the holdup-optimized circuit
of the chromatography unit according to the invention.
[0028] Likewise, by the described discharge of contaminated eluent
fractions in the circulation flow, laborious stoppage or even
startup and shutdown of the unit are avoided. In addition to the
more robust control, this furthermore increases the economy of the
process due to the described invention.
[0029] The more robust separating process of multicolumn
chromatography in countercurrent operation according to the
invention moreover allows a more efficient integration into the
preparation process of chemicals and pharmaceuticals. Thus a
reactor can be connected upstream and the starting material
connected directly as a feed to the multicolumn chromatography
unit. Likewise, recovery of nontarget fractions after further
rearrangements or reactions, such as, for example, re-racemization
by means of pH or temperature shift, are more efficiently possible
in the feed mixture or the reactor.
[0030] A further point is that both the downstream connected
solvent workup and product workup by means of evaporation, drying
and/or crystallization steps can be carried out more efficiently,
since by means of the described invention the throughput is higher,
the product dilution lower and the operating flows more constant;
technically a working point can be chosen which is nearer to the
theoretical optimum.
[0031] In a particularly preferred embodiment, a novel modular
valve system (MVS), which itself is also a subject of this
invention, additionally replaces the known one-way or multiway
fittings and is characterized here by its versatility. The process
paths to be switched can be realized by incorporation of the valve
heads in a single distributor body. In addition, process parameters
(such as, for example, pressure, temperature or concentrations) can
also be determined by means of appropriate adaptations. The MVS is
distinguished by its compact manner of construction, the modular
expandability, cGMP-relevant features (avoidance of dead volumes,
good cleanability) and high ease of maintenance. The valve seats
can be replaced in the most simple manner and adjusted to the
needs. The compactness makes possible very short circuit times with
very high circuit cycles. By means of these significant
improvements, the unit availability on the pilot and production
scale can be markedly increased. Moreover, it is possible using
this invention to operate units nearer to the theoretical optimum
which increases the throughput/the productivity of the entire
unit.
[0032] From WO 03/052308, a valve is already known which is of
modular construction and can be actuated pneumatically. A
characteristic of this valve is an extremely small closing stroke
of the valve spindle. On account of the construction of this valve,
however, only a monodirectional flow of the valve is possible,
whereby this valve is unusable for the use according to the
invention.
[0033] In order to facilitate the simplification of the SMB process
to the process according to the invention and to make possible an
improved and thus preferred embodiment, it was necessary to develop
a valve which has extremely low closing times in the OPEN/CLOSED
position, performs a very large number of switching cycles without
showing wear phenomena, exhibits very low product-side dead spaces,
has small structural dimensions and can be flowed through with
product from both sides, so that in addition to the valve function
in basic use operational cleaning processes by means of reversed
flow directions and CIP (Cleaning in Place) or SIP (Sterilization
in Place) can also be accomplished simply. Moreover, high process
requirements with respect to pressure and temperature must not
restrict the functionality of the valve. In particular in the case
of a circuit of a number of valves in a very small space, it is
absolutely necessary to produce compact valves having few
components in a modular design, which make a very low holdup and
thus sharp separating capacities possible in switching processes.
In spite of a small switching path, the ideal valve should have a
position indicator, by means of which the user can identify the
actual valve position at any time. The automatic or mechanical
switching of the valve to a specified process-side safety position
in the case of control energy outage should in the best case also
still be made possible. No valve known from the prior art can cope
with these requirements in a completely satisfactory manner.
[0034] Surprisingly, however, it is possible to build an MVS which
particularly fulfills the above-mentioned requirements. This MVS
according to the invention consists of a master board (10), on
which at least one valve according to the invention is installed.
The valve according to the invention consists of a valve housing
(20) and a control housing (30), the control housing having an
interior pneumatic space, which is divided into a lower control
space (33) and an upper control space (34) by a piston (31) having
a seal (32). The lower control space is separated from the valve
housing by a closing plate (35) and additional seals (36). On the
piston is located an extended valve spindle (37), which runs
through the valve housing up to the seal seat (11) in the area of
the master board. The valve housing and the control housing are
fixed to one another using a centering plate (21) with seals (22).
The valve housing is positioned relative to the master board using
a second fixing, the seal seat (11) using associated seals (12),
such that a channel connection by means of the seal seat in the
product space of the valve housing is created by means of a supply
channel (13) having a lateral transverse channel (14) in the master
board. From the product space, in turn, a discharge channel (15)
for product discharge is available, by which with the supply
channel together a flow channel is formed. The valve spindle is
bilaterally extended to the piston such that on the one hand the
valve spindle reaches through the upper control space to outside
the control housing and on the other hand the valve spindle is
extended through the valve housing into the seal seat, the valve
spindle having a sealing contour to the valve seat and completely
closing in the closed position the extended transverse channel and
preventing the product flow. The seal seat is positioned with its
seals half in the master board and half in the valve housing, such
that all valve parts are centred and positioned during
installation.
[0035] In addition, a characterizing feature of the MVS is that a
number of valves are arranged in a space-saving manner, such that a
common master board having a common central supply channel can
admit at least two valve seats having an identical number of
transverse channels and forms particularly low dead-space block
valves which make possible the necessary sharp substance separation
in process chromatography by means of appropriate control.
[0036] This type of valve according to the invention is
characterized in a further particular embodiment in that the
pressurized control space and the pressurized product space are
separated by a pressure-less space and as a result leakage
monitoring is made possible.
[0037] The valve according to the invention has a particular seal
contour pairing between the lower, extended valve spindle and the
seal seat, characterized in that different contour pairings and
material pairings combine in order to form concentric seal
contours, which safely prevent product flow in the closed position
of the valve, a round to conical contour pairing preferably being
used.
[0038] Further preferred contours for the valve spindle and seal
seat are concave and or convex designs of spherical and conical
contours, but combination with straight surfaces is also
possible.
[0039] In one particular embodiment, the sealing valve spindle is
designed such that the sealing ends of the valve spindle are
hollowed out in order to employ a complete sphere, to bond both
parts, and to obtain an extremely smooth surface contour for the
sealing function. In a particularly preferred embodiment of the
valve spindle having a sphere, the sphere extends the valve spindle
around the sphere radius and very particularly preferably the
sphere extends the spindle around the half radius.
[0040] Various embodiments of the valves on master boards offer
particular advantages for the acceptance of at least two of the
valve sets according to the invention, the master board being
designed in the form of a square or hexagonal rod and particularly
preferably in spatial shape up to a dodecahedron, the number of
valves situated on the master board being reduced by one to two
based on all surfaces of the master board. By means of the common
master board, it is possible to position two, three, four and more
valves in a very small space, one to two areas having to remain
free on the master board for the central supply and discharge of
the product.
[0041] The extension of the valve spindle by the control housing
makes possible the external application of a position detector,
which signals the current valve position.
[0042] Likewise, a subject of this application is therefore also
block valves which consist of a master board on which at least two
valve housings each having a control housing and in each case
associated internal components, and a position indicator is
attached to each control housing.
[0043] The position indicator makes possible to the operator a
visual indication of the actual valve position, which position
indicator is based on an electrical and or electronic and or
mechanical signal generation, such that an inexpensive visual
position indicator is producible.
[0044] In a preferred embodiment of the valve according to the
invention, the valve seat is situated completely in the master
board.
[0045] The closing stroke of the valve spindle is preferably less
than 5 mm, particularly preferably less than 3 mm and very
particularly preferably less than 1 mm.
[0046] All metallic and nonmetallic materials can be used for the
preparation of the valve.
[0047] In a further embodiment, the valve spindle contours seals
the valve in the seal seat and the diameter course of the
concentric seal area of the two contours is greater than the
hydraulic diameter of the transverse channel, preferably, the seal
range is 1.1 to 1.3 times and particularly preferably the seal area
lies on a diameter in the seal seat of 1.4 to 1.6 times the
hydraulic diameter of the transverse channel.
[0048] The valves according to the invention are particularly
suitable for guaranteeing a reciprocal sharply separating product
flow in process chromatography units. Block valves of small
construction with a central master board are particularly suitable
for use in process chromatography units.
[0049] In process chromatography units according to the invention
which essentially consist of a number of columns connected in
series, the columns arbitrarily having to be capable of being cut
off mutually or to one another, valves are continuously pressurized
by means of the product supply and the product discharge line, in
addition the valves are alternatively switched at short time
intervals in order, for example in the case of different fractions
(product specifications) to make possible a rapid and sharp
separation. Since the products are generally expensive, on account
of the low closing stroke between the OPEN and CLOSED position the
valve according to the invention increases the efficiency of the
entire process chromatography unit. The high valve functionality of
the valves, which is achieved in the form of a high leak tightness
with, at the same time, a high number of switching cycles, is
particularly important. Use in batch chromatography units is
therefore also possible.
FIGURES
[0050] FIG. A shows a four-valve block with master board
[0051] FIG. A' shows the inventive valve with individual
components
[0052] FIG. B shows, by way of example, a hexagonal master board or
rod
[0053] FIG. C shows the preferred concentric seal area
[0054] FIG. D shows a particular design of the sealing valve
spindle contour
[0055] In FIG. A, four inventive valves (1, 2, 3, 4), according to
FIG. A', installed on a common master board, are shown.
[0056] In FIG. A', all individual valve parts are shown on a common
master board (10). It can be seen in FIG. A' that the master board
(10) has a central supply channel (11) for the product and from the
supply channel four transverse channels (14) branch off to the
valves adapted to the master board. At least two further valves can
be installed on the master board, in which a further valve housing
(20) and control housing (30) having appropriate fixing elements
(e.g. screws) are detachably connected to the master board. The
valve housing is centered on the master board by means of the seal
seat (11) and the centering of the control housing is carried out
using a centering plate (21), which engages in the closing plate
(35). In the control housing is a piston (31) having a firmly
connected bilaterally extended valve spindle (37), in order to form
an upper and lower control space (33, 34) in the control housing.
The extended valve spindle extends on the one side up to the seal
seat and on the other side to outside the control housing, in
order, if appropriate, to be able to admit a position detector
outside the valve. The inner parts of the valve are provided with
elastic seals, such that a product flowing through is specifically
conducted by the valve, cannot escape outward, product space and
control space are separate from one another and leakage or failure
of a seal is recognized. In addition, the seals employed serve to
seal individual valve components in their planes. The seal (32) on
the piston separates the upper and lower control space. The two
seals (36) separate the lower control space from the pressureless
valve space, the inner seal sealing to the valve spindle and the
outer seal sealing to the control housing. The centering plate (21)
likewise has two seal (22) in one plane, such that one seals the
product space to the valve spindle and the other prevents a bypass
flow. The centering plate has a transverse drilling (23), which is
extended outwards through the transverse drilling of the valve
housing (24), such that a pressureless intermediate space is formed
between the product space and control space. The transverse
drillings signal a leakage or a failure of the product-side
seals.
[0057] The flowing through of the valve with product takes place by
means of the central supply channel, the transverse channel (14)
and the seal seat, such that the end of the valve spindle contour
is flowed around and the product can flow through the discharge
channel (15) from the valve. The product flowing through is
prevented if, for example, an employed pressure spring (38) in the
upper control space presses the piston with valve spindle into the
contour of the seal seat. The valve opens if, for example, in the
lower control space the attached compressed air builds up pressure
and the compressive force generated is greater than the spring
force in the upper control space, such that the piston is raised,
the valve spindle separates from the seal seat, and a liquid or
gaseous substance can pass.
[0058] In FIG. A, three further positions of the master board are
occupied by valves in order to form a four-block valve.
[0059] FIG. B shows the cross-section of a hexagonal rod or
hexagonal master board (10), the central supply channel (13) and
the transverse channels (14) being incorporated in the hexagonal
master board, and a receiving drilling of the seal seats being
incorporated on each outer surface. FIG. B shows clearly that six
valves with the valve housing (20) and control housing (30) can be
positioned in a narrow space and in the case of a hexagonal rod
even a multiple of six valves one after the other is handleable in
the narrowest space. It is not urgently necessary here, however, to
equip each valve position.
[0060] In FIG. C, the special seal contours of the valve spindle
(37) and of the seal seat (11) are shown. It can be seen that the
preferred seal area (X2-X1) is greater than the hydraulic
cross-section of the transverse channel. This has the advantage
that with a high number of switching cycles at high differential
pressures the sealing contours are not deformed.
[0061] In FIG. D, a special form of the sealing valve spindle
contour (37) is shown. Here, the production of a very smooth
sealing surface is carried out, by way of example, by the
application of a sphere (37'). The sphere projects here partially
into the cross-section of the valve spindle and a part of the
sphere is available elevated as a sealing contour.
[0062] An embodiment of the process according to the invention is
likewise preferred in which a certain mass flow control is
employed, which surprisingly leads to a further performance
increase and is likewise a subject of the present invention.
[0063] In the SMB unit according to the invention, the operating
point is specified by means of the external streams feed Q.sub.F,
extract Q.sub.Ex and raffinate Q.sub.Raf, and the internal eluent
stream Q.sub.I and timing period .tau..
[0064] A mass flow control has now surprisingly been found (see
FIG. 1), in which the mass flows Q.sub.F, Q.sub.Ex, Q.sub.Raf and
Q.sub.I are continuously measured and directly regulated by means
of the speed of rotation of the corresponding pumps (4-pump
procedure). Alternatively, the adjustment of the product streams
Q.sub.Ex and Q.sub.Raf by means of suitable regulating valves
instead of discharge pumps is possible (2-pump procedure). The
adherence of the total mass balance, and thus the correct
adjustment of the desorbent stream Q.sub.D as the remaining
external stream, is also achieved by the filling level regulation
in the eluent receiver. This filling level regulation compensates
the deviations from the nominal mass balance inevitably caused by
disturbances and/or measuring errors and determines, together with
the switching on of the nominal desorbent amount resulting from the
balances,
Q.sub.D.sup.0=Q.sub.Ex+Q.sub.Raf-Q.sub.F+Q.sub.Dest (2)
the flow of freshly added desorbent (eluent):
Q.sub.D=Q.sub.D.sup.0+.DELTA.Q.sub.D.sup.LIC. (3)
[0065] This value is then adjusted by means of the flow regulation
of the desorbent amount and monitored by means of continuous flow
measurement.
[0066] In a very particularly preferred embodiment, a continuous
online analysis measurement QIS is introduced into the recycle line
after zone IV (FIG. 1). In the case of contamination of the solvent
stream fed back (e.g. breakthrough of product from zone IV), this
triggers a corresponding valve circuit, such that the contaminated
solvent stream is discharged and is not fed back into the eluent
receiver.
[0067] The additional flow measurement in the recycle stream
serves, in the case of quality-related discharge of the recycle
stream, for the determination of Q.sub.Dest, in operation as
intended, by the utilization of the redundancy achieved with the
measurement of the flow Q.sub.Dest in the mass flow measurements
and balances, a measurement data validation (data reconciliation)
is performed for all mass flows and thus the accuracy of the mass
flow regulation is additionally increased.
[0068] The mass flow regulation according to the invention makes
possible--in particular by dispensing with a pressure regulation
for the conclusion of the mass balance--a more accurate and more
robust adjustment of the mass flows for the confirmation of the
separating capacity of the unit.
[0069] The very particularly preferred embodiment according to the
invention of a combination of the unit and regulation concept makes
possible both operation with a closed and with an open circulation.
In the case of open circulation, by means of the online analysis
measurement in the recycle line, a possible impurity can be
directly discharged. In the conventional circulation operation,
discharge of impurities is only possible by means of the product
streams and thus associated with a loss of yield.
[0070] The redundancy in the mass flow measurements provided
according to the invention and the measuring error balance for the
flow measurements based thereon additionally increases the accuracy
of the mass flow regulation and thus confirms the fulfillment of
the separation task.
[0071] Using the unit and regulation concept according to the
invention, variable dead volumes and the process disruptions
associated therewith are avoided. Special countermeasures such as,
for example, the asynchronous switching of the valves are thus no
longer necessary.
[0072] The following examples are intended to illustrate the
present invention without, however, restricting it:
[0073] FIG. 5 shows the integration of the multicolumn
chromatography process in an overall process for the preparation of
chemical and pharmaceutical substances as exemplified by racemic
substances. There is the possibility directly, without intermediate
storage after the reaction, leading the reaction mixture
continuously into the chromatography unit. Furthermore, the direct
workup and the recycling of the solvent from the product streams
extract and raffinate into the eluent receiver is possible. The
quality of the eluent must be measured and adjusted before use
again in the chromatography unit. For this, depending on the eluent
composition required, a number of offline methods (such as, for
example, GC and HPLC) and online methods (such as, for example,
ultrasound, capacitative, NIR) are available. From a feed
container, in a further container the feed mixture of solid or
fluid consistency is introduced in the specified eluent
composition. Extract and raffinate are supplied from the
chromatography unit to evaporators and the evaporated solvent is
recycled into the eluent container. Fresh solvent is metered in
from various eluent receiver containers, depending on the number of
solvents involved in the eluent mixture, until the required eluent
specification is achieved in the eluent supply to the
chromatography unit. The concentrated product after evaporating is
stored in containers and generally crystallized, filtered and dried
in the further product workup. The byproduct--in the example case
the "wrong" enantiomer--is usually re-racemized for economic
reasons (often, for example, by pH or temperature change) and after
quality control added to the feed mixture derived from the original
reaction stage.
* * * * *